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Projects for Technological Development

First Year FY2013
Title Development of cell transplantation methods for refractory muscle diseases
Principal Investigator Shin'ichi Takeda
(Director, Translational Medical Center, National Center of Neurology and Psychiatry)
Subsidiary institution Kyoto University, Osaka University, Fujita Health University
Summary The aim of this research is to establish methods for transplantation of muscle stem cells derived from human induced Pluripotent Stem (iPS) cells, for development of regenerative medicine for muscular dystrophy and other refractory muscle diseases. A lot of efforts have been made to develop therapies toward Duchenne muscular dystrophy (DMD), a typical hereditary muscle disease caused by the mutations in the Dystrophin gene, however no curative treatment has been developed so far, which is applicable to all genetic types of DMD. Transplantation of muscle-derived stem cells has been done in DMD mouse models, but human muscle stem cells are hard to be induced in sufficient quality and quantity for clinical use. In this study, we aim to establish stem cell transplantation therapy applicable to refractory muscle diseases including DMD by optimize methods for differentiating iPS cell into muscle stem cells, culturing and purifying them, and transplanting them to host muscle tissue.
First Year FY2013
Title Development of new diabetes treatments using human induced pluripotent stem (iPS) cells
Principal Investigator Yoshiya Kawaguchi
(Professor, Center for iPS Cell Research and Application, Kyoto University)
Summary The aim of this research topic is to establish a method for generating functional pancreatic cells from iPS cells. Various pathologies, including nephropathy, retinopathy, and neurological and cardiovascular disorders, have diabetes as the underlying disease, and, although considerable progress has been made with drug therapy for diabetes, pancreas or pancreatic islet transplantation is considered to be essential for radical treatment of type 1 diabetes, caused by insulin deficiency. However, numerous patients are currently waiting for such transplants, and there is a chronic shortage of donors. The hypothesis put forward on the basis of developmental biology and the long-term results of clinical pancreatic islet transplantation is that “In order to generate functional pancreatic cells, there is a need for both the three-dimensional structure (the pancreatic pseudo-islet structure), and the presence of exocrine cells”. For this reason, the current aim is to create a whole pancreas.
First Year FY2013
Title Development of automated 3D suspension culture technology for its practical application in regenerative medicine
Principal Investigator Katsumi Nakashima
(Senior Manager, Marketing Division, Kawasaki Heavy Industries, Ltd.)
Subsidiary institution Sumitomo Bakelite Co., Dainippon Sumitomo Pharma Co., Sumitomo Chemical Co.
Summary The goal of this research is to automate three-dimensional suspension culture of stem cells. Three-dimensional suspension culture is an important technique for producing cells and three-dimensional tissues that are useful for regenerative medicine. However, compared to two-dimensional culture technique, three-dimensional culture technique is much more difficult, and there have been delays in development of the technique for practical application. In this research, we will collaborate with research centers for practical application, by disease and/or tissue, and also take advantages of Kawasaki Heavy Industries Ltd.’s accumulated technology for liquid handling and its vessel handling technology applied from leading-edge robot technology, Sumitomo Bakelite Co.’s innovative technology development for labwares such as culture vessels, and quality assessment technology of Dainippon Sumitomo Pharma Co. and Sumitomo Chemical Co. We will simplify operations by modifying labwares and then achieve high throughput processing for automated cell culture by automating and parallelizing the simplified operations.
First Year FY2013
Title Development of organ regeneration techniques and new transplantation methods, using stem cell packaging
Principal Investigator Yuko Kitagawa
(Professor, School of Medicine, Keio University)
Subsidiary institution Jichi Medical University, University of Tokyo
Summary Organ decellularization is a novel technique for regenerative therapy by removing all the viable cells and thus retaining only the matrix scaffold. We have developed this technique in human-scale to achieve clinical application of liver transplantation using induced pluripotent stem cells with structural maintenance of native organ scaffolds using large animals. In this project, we aim to provide widely applicable method for clinical use of iPS cell technologies that have been developed in the other project groups. The specifications are to be defined for all processes from decellularization to transplantation in human-scale, and aseptic packaging methods enabling final product are to be established. On the basis of this project, we expect to establish three-dimensional native scaffolds for achievement of blood circulation, to stabilize the process steps as far as transplantation and to expand these to fundamental technologies to accelerate the realization of regenerative medicine.
First Year FY2013
Title Development of culture substrates for stem cells
Principal Investigator Kiyotoshi Sekiguchi
(Professor, Institute for Protein Research, Osaka University)
Subsidiary institution Nippi, Inc.
Summary The aims of this research topic are to develop culture substrates appropriate for culture and induction of differentiation of human induced pluripotent stem (iPS) cells for use in regenerative medicine, and to take up a position enabling stable supply of these substrates. For the purpose of medical application of iPS cells and other human pluripotent stem cells, culture techniques enabling safe and stable culture and amplification of these cells, and efficient induction of differentiation of specific cells, are essential. In the human body, scaffold proteins differ between cell types, and optimization for each cell type is therefore also essential for proteins used as culture substrates. The aims of this research topic are thus to try to identify the optimal scaffold proteins for each cell type, and to develop culture substrates for maintenance of iPS cells in an undifferentiated state, for induction of differentiation by iPS cells, and for differentiation- induced cells for use in epithelioid cell sheet manufacture. An additional aim is to develop technology for preparation of culture substrates as final products, in accordance with good manufacturing practice.
First Year FY2013
Title Generation of functional kidney cells and tissues from human induced pluripotent stem (iPS) cells towards development of regenerative medicine strategy for chronic kidney disease
Principal Investigator Kenji Osafune
(Professor, Center for iPS Cell Research and Application, Kyoto University)
Subsidiary institution Yokohama City University, National Institute of Biomedical Innovation
Summary The aim of this research project is to develop methods for generating functional kidney cells and tissues from human iPS cells towards realization of regenerative therapies for chronic kidney disease (CKD). The estimated prevalence of CKD is as high as one in eight Japanese adults. Due to the paucity of radical treatment methods, it is desirable that regenerative medicine strategies will be developed for CKD, but methods for inducing differentiation of human embryonic stem (ES) or iPS cells to form kidney cells have not yet been established anywhere in the world. In the present research, we will aim to establish methods for inducing differentiation of human iPS cells into fetal kidney precursor cells, and adult renal cells, such as glomerular, renal tubular, and collecting duct epithelial cells, and to develop methods for generation of vascularized, functional kidney tissues. In addition, using an animal model of kidney failure, fundamental research is to be carried out on regenerative therapies using transplantation of kidney cells and tissues derived from human iPS cells.
First Year FY2013
Title Establishment of a transplantable immunotolerant-cynomolgus macaque colony, and application to regenerative medicine
Principal Investigator Kazumasa Ogasawara
(Professor, Dept. of Pathology, Shiga University of Medical Science)
Subsidiary institution Tokai University, Kyoto University
Summary The aims of this research topic are to establish a platform that provides transplantable immunotolerant-cynomolgus macaques that are usable as a preclinical study model for the induced pluripotent stem (iPS) cell-stock concept. iPS cells and iPS-derived cells prepared from major histocompatibility complex (MHC) –homozygous animals are expected to induce almost no rejection reactions when transplanted into MHC-heterozygous animals. The iPS cell-stock concept is based on this principle, for which a preclinical study model is necessary before transferring it to clinical application. To this end, this research plans to use MHC-heterozygous macaques and iPS cells prepared from MHC-homozygous cynomolgus macaques. We will expand the transplantable immunotolerant- cynomolgus macaque colony, so as to establish a platform that can supply preclinical-study macaques to a wide range of researchers both within and outside the network of regenerative medicine realization centers, for progress toward regenerative medicine using iPS and iPS-derived cells. At the same time, we plan to establish a diabetes model using immunotolerant cynomolgus macaques, and to elucidate the effects of diabetes pathology on iPS cells, in order to develop next generation of diabetes therapy using iPS cells.
First Year FY2013
Title Quantum-switching in vivo theranostics for induced pluripotent stem (iPS) cell differentiation and carcinogenesis
Principal Investigator Yoshinobu Baba
(Professor, Graduate School of Engineering, Nagoya University)
Subsidiary institution Kyoto University
Summary The aims of this research are to create quantum/magnetic nanoparticulate hybrid materials, and to achieve in vivo theranostics (combining diagnosis and therapy) for iPS cell carcinogenesis and differentiation by quantum-switching. In order to make progress with clinical application of iPS cells, the establishment of techniques for diagnosis of carcinogenesis and differentiation as well as iPS cell kinetics and for elimination of abnormal cells is strongly expected. In this research, capsulation technology based on safe quantum dots, magnetic nanoparticles, and biocompatible materials for iPS cells is developed. Moreover, quantum/magnetic nanohybrid materials, which enable diagnosis of in vivo carcinogenicity, differentiation and elimination of abnormal cells by quantum-switching and magnetic effects, are created. The efficacy of this technology for treating bone, cartilage and liver diseases is confirmed, and the clinical application of iPS cells is accelerated by the development of this technique.
First Year FY2013
Title Development of technology for rapid quantification of the heterogeneity of induced pluripotent stem (iPS) / differentiated cell populations with both single-cell and whole-transcriptome resolution
Principal Investigator Itoshi Nikaido
(Unit Leader, Advanced Center for Computing and Communication, RIKEN)
Summary This research topic involves developing technology for confirmation and evaluation of the cellular heterogeneity of human iPS cells and iPS-derived differentiated cells, and dramatically increasing the safety and efficacy of regenerative medicine. iPS/differentiated cells include cells of different cellular states, even in colonies with consistent culture conditions. However, the degree of heterogeneity, and its effects on cell transplantation, are not fully understood. In order to verify and control cellular heterogeneity, the first step is to quantify the heterogeneity of cell populations. Therefore, the cellular-state parameters measured must be single-cell values rather than population means. In the present research topic, technology for rapid quantification of the heterogeneity of iPS/differentiated cell populations, with both single-cell and whole-transcriptome resolution, is to be developed. Therefore, the aims are to carry out detailed analysis of the single-cell expression level, and to develop a data-analysis method for judging the heterogeneity of the data obtained.
First Year FY2013
Title Development of induced pluripotent stem (iPS) cell bulk culture platform for use in regenerative medicine
Principal Investigator Hiromichi Kumagai
(Fellow, Kumagai Fellow Laboratory, Research Center, Asahi Glass Co.,LTD.)
Summary The aim of this research is to establish the platform technology needed for bulk culture and stable supply of undifferentiated iPS cells, and to contribute to rapid achievement and international expansion of regenerative medicine. For practical application of this technology, it is essential to establish manufacturing protocol in compliance with various regulations, with consideration given to safety and robustness from an early stage of development. To date, various types of protein-based drugs have been manufactured in accordance with precise drug production management, and good manufacturing practice (GMP). In the present research, human transferrin, and various growth factors and extracellular matrix components will be manufactured economically in accordance with GMP using genetically recombinant technology with a small risk of contamination by extraneous viruses., Furhtermore,bulk culture vessels and the platform technology for iPS cell culture is to be provided. This research and development is expected to contribute the realization of regenerative medicine.
First Year FY2013
Title Methods of cell-transdifferention technology based on defined factors, in order to regenerate heart function
Principal Investigator Jun Takeuchi
(Associate Professor, Institute of Molecular and Cellular Biosciences, The University of Tokyo)
Subsidiary institution Kyoto University
Summary Cardiac dysfunction, such as heart failure, is one of leading causes of death worldwide. Potentially effective new therapy would be to introduce factors that prevent cardiac cells from deteriorating and/or to introduce fresh cardiac cells themselves to affected areas. To this end, this research will address the following three themes, so as to establish simple, rapid and reliable regeneration of cardiac cells:
1. Programming:
The aims are to establish technology to induce fully-differentiated single-species cardiac cells, including cardiac precursor cells, atrial and ventricular cells, and pacemaker cells, directly from induced pluripotent stem cells, and to provide these cells as transplantable cells, or as analysis tools for elucidation of the pathology of heart disease, to clinical research centers and clinical institutions.
2. Reprogramming:
The aims are to propose novel myocardial introduction methods that do not involve transplantation, by identifying the factors that transforms cell destiny, for myocardial regeneration in areas affected by heart disease, and thus to rejuvenate the myocardium.
3. Development of vector cassettes for gene introduction:
To translate these technologies to clinical settings, we will develop vectors for the programming and reprogramming, which are suitable for use in humans.
First Year FY2013
Title Development and commercialization of technologies for rapid, efficient, high-quality, and large-scale production of a variety of differentiated cells from pluripotent stem cells
Principal Investigator Minoru Ko
(Professor, School of Medicine, Keio University)
Summary The aims of this research project are to develop and test technologies for efficient generation of various types of differentiated cells from human pluripotent stem cells (embryonic and induced pluripotent stem cells). Previous methods for cell differentiation were primarily dependent on the long-term cell cultures in the media optimized for specific cell types. However, to further advance regenerative medicine, it is desirable to develop new technologies for rapid and efficient generation of a variety of differentiated cells from human pluripotent stem cells. In the present research, we plan to test a large number of transcription-regulating factors and their combinations for their abilities to efficiently differentiate human pluripotent stem cells. Once these factors are identified, we propose to develop cocktails of these factors for research use as well as for commercialization.
First Year FY2013
Title Development of novel quality-evaluation techniques for regenerative medical agents derived from induced pluripotent stem (iPS) cells and somatic stem cells
Principal Investigator Tomohiro Morio
(Professor, Dept. of Pediatrics and Developmental Biology, Tokyo Medical and Dental University)
Subsidiary institution Kazusa DNA Research Institute, National Institute of Health Sciences
Summary The aims of the present research topic are to establish and validate a systematic, rapid microorganism-detection system, and a genetic stability verification system, as next-generation quality-assurance technology for regenerative medical agents derived from iPS cells and somatic stem cells. There is a need for systems enabling rapid, low-cost and high-sensitivity verification of genetic instability with iPS cell preparations, and microorganism contamination and amplification with cell preparations. With respect to microorganism-detection systems, polymerase chain reaction systems covering the important viruses, and the mycoplasma species specified by the Japanese, US and EU regulatory authorities, are to be established, and test systems that enable judgment about bacteria and fungi on the actual preparation date are to be developed. The ultimate aims are to develop kits for quantification of all microorganism species with a single platform, and to develop, as genetic stability verification systems, innovative quantification systems for detection of mutation accumulation, gene loss, and gene modification with small numbers of cells.
First Year FY2013
Title Development of induced pluripotent stem (iPS) cell technologies utilizing pigs and other large mammals
Principal Investigator Yutaka Hanazono
(Professor, Division of Regenerative Medicine, Center for Molecular Medicine, Jichi Medical University)
Summary The aim of this research is to prepare hematopoietic stem cells, erythrocytes, and platelets from human iPS cells, utilizing pigs and other large mammals. Most researches aimed at organ regeneration from human iPS cells are currently focused on in vitro differentiation-induction studies. The in vitro differentiation-induction efficiency, however, is not necessarily high. Furthermore, organogenesis and in vivo differentiation are not fully reproducible in vitro. A potential method to overcome these difficulties is to produce organs in animals. Thus, the present research aims to produce iPS cell-derived hematopoietic stem cells, erythrocytes, and platelets inside pigs and sheep, through the use of clinically friendly iPS cells that are safe and superior in growth and differentiation capabilities.
First Year FY2013
Title Development of human induced pluripotent stem cell culture apparatus toward mass manufacturing of regenerative medicine products
Principal Investigator Katsuhisa Matsuura
(Associate Professor, Institute of Advanced Biomedical Engineering and Science, Tokyo Women’s Medical University)
Subsidiary institution Able Co., Asahi Kasei Corp.
Summary The aims of this research topic are to develop culture apparatus toward mass manufacturing of products for use in regenerative medicine, using iPS cells. The present researchers have already developed three-dimensional agitated-suspension culture technology applicable to human iPS cells, and technology for high-density undifferentiated amplification from the single-cell state. In addition, technology for high-density and high-yield cardiac induction of human iPS cells, and technology for applying cell sheets to construction of human myocardial tissue, have been developed. The aims of the present research are to improve and expand upon specific techniques developed by the present researchers, and, on the basis of collaboration with centers researching practical applications to different diseases and tissues, to make supply-side and technology-side contributions to first-in-human myocardial studies using human iPS cells. Additional aims are to develop technology for automation of all processes involved in undifferentiated and differentiation-induced cultures, and culture apparatus to enable stable and reliably safe supply of raw materials for regenerative medicine products.
First Year FY2013
Title Development of inductive technologies for three-dimensional ectodermal organs including teeth, exocrine glands and other ectoderm-derived organs through regulations of epithelial and mesenchymal interactions
Principal Investigator Takashi Tsuji
(Team Leader, Center for Developmental Biology, RIKEN)
Subsidiary institution Organ Technologies, Inc.
Summary The aims of the present research topic are to develop, from induced pluripotent stem (iPS) cells, inductive technologies for ectodermal organs (teeth and exocrine glands), based on precise controls of epithelial and mesenchymal interactions in three dimensional stem cell culture in vitro. Tooth loss and exocrine gland disorders, such as dry-mouth and dry-eye diseases, can only be treated by symptomatic treatments and/or replacement with artificial material. It is therefore expected to develop novel regenerative therapies enabling fundamental restoration of those organ functions. In this topic, we induce epithelial and mesenchymal stem cells from human iPS cells, and develop bioengineered ectodermal organs by using the Organ Germ Method, which is a precise three dimensional cell manipulation technique to reconstitute bioengineered organ germs, on the basis of collaboration with other research centers involved in practical application for different diseases and tissues. In addition, we aim to develop a novel three dimensional organ culture system for realization of fully-functional organ replacement regenerative therapy.
First Year FY2013
Title Construction of resources for cell system-control gene expression for regenerative medicine
Principal Investigator Naoki Goshima
(Team Leader, Molecular Profiling Research Center for Drug Discovery, National Institute of Advanced Industrial Science and Technology)
Subsidiary institution Japan Biological Informatics Consortium
Summary In regenerative medicine, cell system-control techniques based on gene introduction are very important for induction of pluripotent stem cells, induction of differentiation, direct reprogramming of somatic cells, etc. A Human Protein Expression Resource (HuPEX) covering approximately 80% of the entire human genome has already been established. In the present research a database will be prepared by prioritized collection of site- and time-specific cDNA, including splicing variants, relating to cell initialization, differentiation, etc. On the basis of collaboration with each research center, clones expressing cell system-control genes are to be prepared, and research on regenerative medicine is to be speeded up by establishing a supply system. In addition, functional proteomic analysis of those cell system-control genes requiring attention is to be carried out, making full use of unique protein arrays.
First Year FY2013
Title Development of methods for differentiation induction and transplantation of hypothalamic and pituitary hormone-producing cells, using human induced pluripotent stem (iPS) cells
Principal Investigator Hidetaka Suga
(Clinical Assistant Professor, Nagoya University Hospital, Nagoya University)
Subsidiary institution Fujita Health University
Summary The aims of this research topic are to prepare hypothalamic and pituitary tissues from human iPS cells, and to establish effective transplantation techniques with clinical application as the goal. The hypothalamic-pituitary system is essential for maintaining life and for controlling systemic homeostasis, but is negatively affected by various diseases, leading to serious symptoms. For replicating the complex and precise control of the hypothalamic-pituitary system, there are hopes for regenerative medicine using pluripotent cells. This research group has previously established techniques for preparing hypothalamic vasopressin cells and anterior pituitary tissue from murine embryonic stem cells. The aims of the present research are to develop techniques for producing such cells from human iPS cells; to establish transplantation techniques; to carry out preclinical research with disease-model mammals; and thus to clearly demonstrate the efficacy of transplantation, making progress toward clinical application.
First Year FY2013
Title Development of techniques for maintenance and amplification of hepatic stem/precursor cells derived from human induced pluripotent stem (iPS) cells toward hepatocyte transplantation
Principal Investigator Hiroyuki Mizuguchi
(Professor, Graduate School of Pharmaceutical Sciences, Osaka University)
Subsidiary institution ReproCELL, Inc.
Summary The aim of the present project is to prepare transplantable hepatocytes from human iPS cells. As radical therapy for cirrhosis and various other liver diseases, hepatocyte transplantation has been shown to be effective, but, due to the need for a large quantity of hepatocytes per patient, there is a shortage of donors. Attention has recently been given to human iPS cell-derived hepatocytes as a new source for transplantation. However, a long time is currently needed for preparation of hepatocytes from human iPS cells, and the production of large amounts of human iPS cell-derived hepatocytes is therefore difficult. In the present research, we try to develop techniques to maintain and amplify hepatic stem/precursor cells, which are precursors of hepatocytes, using a defined serum-free medium and optimized laminin. These techniques should be useful for hepatocyte transplantation and other aspects of regenerative medicine.
First Year FY2013
Title Development of angiogenesis control techniques for regenerative medicine
Principal Investigator Nobuyuki Takakura
(Professor, Research Institute for Microbial Diseases, Osaka University)
Summary On the basis of angiogenesis being an essential phenomenon for organ regeneration, the aim of this research topic is to develop techniques not only to link regenerated organs to the general circulation, but to rapidly induce the growth of hepatic sinusoids and other organ-specific blood vessels within regenerated organs. The present researchers have recently demonstrated the presence of endothelial stem cells within existing blood vessels, and have shown that organ-specific vascular structures are formed from these stem cells, and that large-diameter vessels are formed from these stem cells alone. The aims of the present research are to develop, on the basis of the above findings, techniques for in vitro amplification of endothelial stem cells that are present in the human body in only very small numbers, and techniques for bulk recovery of endothelial stem cells. An additional aim is to apply vascular maturation mechanisms, and thus to develop techniques enabling formation of vascular units with control of arteries and veins, with endothelial cells as the cell source.
Research Center Network for Realization of Regenerative Medicine
Japan Agency for Medical Research and Development(AMED)
Regenerative Medicine Division,
Department of Strategy Promotion


1-7-1 Otemachi, Chiyoda-ku,Tokyo, 100-0004 Japan
Phone: +81-3-6870-2220
E-Mail:saisei-ML@amed.go.jp
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